1. Field of the Invention
The processes of the present invention produce compounds both old and new which are useful intermediates in the synthesis of .beta.-lactam antibiotics.
2. Description of the prior art
Penicillins and cephalosporins comprise a group of well-known antibacterial agents commonly grouped together as a class called .beta.-lactam antibiotics. For a recent review of this field with many citations (especially the first ten) to the prior work see J. P. Hou and J. W. Poole, .beta.-lactam Antibiotics: Their Physicochemical Properties and Biological Activities in Relation to Structure, J. Pharmaceutical Sciences, 60(4), 503-532 (April, 1971). Most of the work in this field has fundamentally been done, speaking broadly, with 6-aminopenicillanic acid, 7-aminocephalosporanic acid and derivatives thereof produced by fermentation.
Considerable work has also been done on total chemical synthesis. A recent review is the text by M. S. Manhas and A. K. Bose, Synthesis of Penicillin, Cephalosporin C and Analogues, Marcel Decker, Inc., 95 Madison Avenue, New York, N.Y., 1969. An even more recent review is by R. B. Morin and B. G. Jackson, Chemistry of Cephalosporin Antibiotics, Fortschr Chem. Org. Naturst, 28, 343-403 (1970), especially pages 379-393; the now famous "Woodward Intermediate" is shown therein as Compound 146 on page 387.
Within recent months publications describing new work and summarizing and citing older work have appeared such as:
A. FROM Imperial College, London, and Glaxo jointly by D. H. R. Barton et al., J. Chem. Soc. (C), 1971, 3540-3550;
b. from Oxford University by D. M. Brunwin et al., J. Chem. Soc. (C), 1971, 3756-3762;
c. from The University, Newcastle upon Tyne, by B. G. Ramsay and R. J. Stoodley, J. Chem. Soc. (C), 1971, 3859-3867;
d. from Lilly by S. Kukolja, J. Amer. Chem. Soc. 93, 6267-6270 (1971);
E. FROM Lilly by G. E. Gutowski et al., Tetrahedron Letters No. 37, 3433-3436 (1971);
F. FROM Lilly a series of papers entitled Chemistry of Cephalosporin Antibiotics, e.g. No. 25 in J. Medicinal Chemistry 14(11), 1136-1138 (1971) and No. 21 in J. Org. Chem., 36(9), 1259-1267 (1971).
The anhydropenicillins used as starting materials in the present invention were first described by Saul Wolfe in J. Amer. Chem. Soc. 85, 643-644 (March, 1963), Belgium 621,452 and U.S. Pat. No. 3,311,638. Additional publications on anhydropenicillins by Saul Wolfe include Can. J. Chem. 46, 459 and 2549 (1968).
Various azetidinones have been disclosed in patents such as Sheehan's U.S. 3,487,070-072 (Class 260-239) and 3,487,090 (Class 260-326) and, for example, Woodward's U.S. Pat. 3,483,215 (Class 260-306.7) and U.S. Pat. 3,449,336 (Class 260-243).
The oxazoline having the structure ##EQU1## which is more commonly written as ##SPC1##
has been prepared from the methyl ester of benzylpenicillin in 18% yield, as by Barton et al., J. Amer. Chem. Soc., 91, 1529 (1969), and (a) above. Only one other bicyclic, sulfur-free compound of this type has been described [by E. G. Brain et al., J. Chem. Soc. Chem. Comm., 229-230 (1972)] but a rational synthesis of such esters or acids has not appeared.
The stereochemistry of the methyl ester of benzylpenicillin (i.e. the penicillin G produced by fermentation) is represented as follows: ##SPC2##
Kukolja [J. Amer. Chem. Soc. 93, 6267-6270 (1971)] chlorinated (with 2 equivalents of chlorine) methyl 6-phthalimidopenicillanate ##SPC3##
to produce a mixture of the two epimers having the structure ##SPC4##